Feed additive for improving growth in agricultural animals

ABSTRACT

By using .sub.α -mimetics, particularly compounds of general formulae I to III and the compounds listed in Table I, as feed additives in fattening animals, it has surprisingly been possible to improve the daily weight gain, the utilization of fodder and the ratio of muscle to fat in favor of the proportion of muscle and protein.

This is a division of application Ser. No. 252,209, filed Oct. 25, 1988,now U.S. Pat. No. 4,970,208, which in turn is a division of applicationSer. No. 019,447, filed Feb. 26, 1987, now U.S. Pat. No. 4,808,402,which is in turn a continuation of application Ser. No. 760,239 filedJul. 30, 1985, now abandoned.

1. Field of the Invention

The invention relates to feed additives for improving growth inagricultural animals.

2. Background of the Invention

Sympathomimetics impart their effects via α and β receptors. Of thesympathomimetics, there are natural and synthetic substances which arepredominantly effective either via β or via α receptors.

The activity of sympathomimetics which act predominantly via α receptorsconsists, for example, in the contraction of the smooth muscle of theblood vessels and uterus, the sphincters in the gastrointestinal tractand the M. dilatator Pupillae (mydriasis). They also have a relaxanteffect on the longitudinal muscle of the gastrointestinal tract andcause glycogenolysis in the liver.

The α-mimetics are known to be useful systemically for producinghypotensive regulation of the circulation, and locally for reducinginflammation of the mucous membranes in the nose, for stopping diffusingbleeding, as a mydriatic and as an additive to local anaesthetics.

It is known that in some species of laboratory animals, intravenousadministration of clonidine results in a brief (limited to a few hours)but substantial increase in the production of growth hormones and thatintramuscular administration in monkeys leads to an increase in appetiteand a consequent increase in food intake and a brief weight gain. Thefood intake in rats has also been shown to increase after intracerebraladministration of this drug.

SUMMARY OF THE INVENTION

It has now been found that α-mimetics are useful as additives in feedfor agricultural animals. Animals raised on feed containing α-mimeticadditives exhibit increased weight gain and utilize fodder moreefficiently than is the case with regular feed.

In particular, those α-mimetic imidazolines of formula I, imido[1,2-a]striazines of formula II, azepines of formula III, as described fullyherein, the compounds listed in the following Table I, as well as thephysiologically acceptable acid addition salts thereof, are especiallyuseful as feed additives in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

The imidazolines useful as feed additives according to the invention areof the formula ##STR1## wherein: R¹ is hydrogen, alkyl ortetrahydropyran;

R² is hydrogen, benzoyl or acetonyl;

A is a carbon or nitrogen;

Y is hydrogen, a halogen atom, such as, for example, F, Cl or Br, alkyl,haloalkyl, alkoxy, haloalkoxy, amino, nitro, hydroxy, alkylthio,halothio, or cyclopropyl; and,

X and Z are the same or different and each is hydrogen, a halogen atom,such as, for example, F, Cl or Br, alkyl, haloalkyl, alkoxy, haloalkoxy,amino, nitro, hydroxy, alkylthio, or halothio; or,

X and Z together form

    ═N--S--N═,

    --N═(CH.sub.2)═N--,

    ═N--N(CH.sub.3)--CH═, or

    --(CH.sub.2).sub.4 --.

The imidazo[1,2-a]s-triazines useful as feed additives are those of theformula ##STR2## wherein: R¹ is unsubstituted phenyl or phenyl which ismono-, di-, or tri-substituted by halogen atoms, preferably fluorine,chlorine or bromine atoms, methyl, methoxy, or trifluoromethyl, thesubstituents on said phenyl being the same or different; and,

R² is hydrogen, phenyl, or phenyl which is mono- or poly-substituted byhalogen atoms, preferably chlorine atoms.

The azepine derivatives useful as feed additives are those of theformula ##STR3## wherein: R¹ is hydrogen, straight-chained or branchedC₁₋₄ alkyl which may optionally be substituted by hydroxyl, allyl,cycloalkyl, hexahydrobenzyl, phenyl, phenylethyl or benzyl, wherein suchbenzyl group may be substituted in the nucleus by one or two halogenatoms, by one to three methoxy groups, by a trifluoromethyl group orC₁₋₃ alkyl and, if

X is sulphur, then R² is hydrogen, straight-chained or branched C₁₋₅alkyl, allyl, cycloalkyl, phenyl, benzyl or phenylethyl or, if

X is oxygen, then R² is hydrogen.

Further compounds useful as feed additives are given in the followingtable.

                  TABLE 1                                                         ______________________________________                                        1)   2-[1-(2,6-Dichlorophenoxy)ethyl]-2-imidazoline                                 ##STR4##                                                                2)   2-[(2-Chloro-4-methyl-3-thienyl)amino]-2-imidazoline                           ##STR5##                                                                3)   2,6-Dichlorophenylacetylguanidine                                              ##STR6##                                                                4)   1-(2,6-Dichlorobenzylideneamino)guanidine                                      ##STR7##                                                                5)   2-(2,6-Dimethylbenzylamino)-4,5-dihydro-6H-1,3-                               thiazine                                                                       ##STR8##                                                                6)   2,6-Dichlorobenzaldehyde-(4-amino-4H-1,2,4-                                   triazol-3-yl)-hydrazone                                                        ##STR9##                                                                7)   2-(2,6-Dichlorophenyl)-5,6-dihydroimidazo-[2,1-b]-                            thiazole                                                                       ##STR10##                                                               8)   4-(2,6-Dimethylbenzyl)imidazole,                                              1-(Imidazol-4-yl)-2-(2,6-dimethylphenyl)-ethane,                              1-(Imidazol-4-yl)-3-(2,6-dimethylphenyl)-propane,                             1-(Imidazol-4-yl)-4-(2,6-dimethylphenyl)-butane                                ##STR11##                                                               9)   6-(2,6-Dichlorophenyl)-2,3,6,7-tetrahydro-5H-                                 pyrrolo[2,1-b]imidazole,                                                      6-(2-Chloro-6-fluorophenyl)-2,3,6,7-tetrahydro-5H-                            pyrrolo[2,1-b]imidazole,                                                      6-(2,6-Dichloro-3-methylphenyl)-2,3,6,7-tetrahydro-5H-                        pyrrolo[2,1-b]imidazole                                                        ##STR12##                                                               10)  2-(4-t-Butyl-2,6-dimethyl-3-hydroxy-benzyl)-                                  2-imidazoline                                                                 2-(4-t-Butyl-2,6-dimethyl-benzyl)-2-imidazoline                                ##STR13##                                                               11)  2-(1,2,3,4-Tetrahydro-1-naphthyl)-2-imidazoline                                ##STR14##                                                               12)  2-(1'-Naphthylmethyl)-2-imidazoline                                            ##STR15##                                                               13)  2-(2-Methoxy-5-chlorophenyl)azoimidazole                                       ##STR16##                                                               14)  2-[N-(4-Hydroxy-2-methylbenzylidene)hydrazino]-                               2-imidazoline                                                                  ##STR17##                                                               15)  2-Dimethylamino-5,6-dihydroxy-1,2,3,4-tetrahydro-                             naphthalene                                                                    ##STR18##                                                               16)  5-Chloro-4-(2-imidazolin-2-ylamino)-2,1,3-                                    benzothiadiazole                                                               ##STR19##                                                               17)  4-(2-Imidazolin-2-ylamino)-2-methyl-benzopyrazole                              ##STR20##                                                               18)  2-Amino-1-(2,5-dimethoxyphenyl)-propanol                                       ##STR21##                                                               19)  1-(3-Hydroxyphenyl)-2-methylamino-ethanol                                      ##STR22##                                                               20)  2-[(O-Cyclopropylphenoxy)methyl]-2-imidazoline                                 ##STR23##                                                               21)  3'-(1-Hydroxy-2-methylaminoethyl)methanesulphonanilide                         ##STR24##                                                               22)  2-Amino-5-methylthio-8-methoxy-1,2,3,4-tetrahydro-                            naphthalene                                                                    ##STR25##                                                               ______________________________________                                    

Of the group of formulae I-III the following compounds are preferred:

1) 2-(2,6 dichloroanilino)-2-imidazoline;

2) 8-(2,6 dichlorophenyl)-7-(4-chlorophenyl)5-oxo-2,3-dihydro-imidazo[1,2-a]s triazine;

3) 1-acetonyl-2(2,6-dichlorophenylamino) 2-imidazoline;

4) 2 (2-bromo-6-fluoroanilino)-2-imidazoline;

5) 2 (2-fluoro-6-trifluoromethylphenylamino)-2-imidazoline;

6) 2 (2-chloro-5-trifluoromethylphenylamino) 2-imidazoline;

7) 2-(2-chloro-4-cyclopropylphenylamino) 2 imidazoline;

8) 2-(3-fluoro-4-methylphenylamino)-2-imidazoline;

9) 2-(6-chloro-4-methoxy-2-methyl-pyrimidin-5-yl-amino)-2 imidazoline;

10) 1-benzoyl-2-(2,6-dichloroanilino)-2-imidazoline;

11) 2 [N (2,6 dichlorophenyl)-N-tetrahydropyran2-yl)-amino]-2-imidazoline;

12) 5-chloro-4-(2-imidazolin-2-yl-amino) 2,1,3-benzothiadiazole;

13) 2-(1,2,3,4-tetrahydro-5-naphthylamino)-2 imidazoline;

14) 2 (4-amino-2,6-dichlorophenylamino)-2 imidazoline;

15) 4 (2-imidazolin 2-yl amino)-2-methyl 1,2-benzo pyrazole;

16) 2-(3,4-dihydroxy-phenylamino)-2-imidazoline;

17) 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H oxazolo[5,4 d]-azepine;

18) 2-amino-6-(p-chlorobenzyl)-4,5,7,8-tetrahydro6H-thiazolo[5,4-d]azepine;

19) 2-(4 bromo-quinoxalin-5 yl-amino-2 imidazoline;

The foregoing compounds of formulae I-III and those listed in Table Iare either grown per se or can be readily synthesized.

It has been unexpectedly found that animals fed with feed comprisingα-mimetics in accordance with the invention, particularly the g mimeticsof formulae I-III and the compounds listed in Table I, exhibit improvedweight gain, even where food intake is reduced. Further, slaughteryields are increased and the carcasses are improved inasmuch as theratio of muscle to fat is increased. There is no detrimental effect onthe quality of the meat.

These effects in agricultural animals are achieved by dailyadministration through the fodder or by parenteral systems with delayedrelease of the active substance.

One particularly surprising feature is the fact that the improvedperformances observed can be maintained over fairly long periods oftime, something which could not have been predicted on the basis of theendocrinal counter-regulatory measures to be expected.

Thus, the activities described above can remain fully effectivethroughout the periods of fattening or performance typical for eachspecies of animal.

α-Mimetics thus constitute a valuable aid in animal production.

For this purpose, according to the invention, a compound as describedhereinbefore is added in a concentration of from 0.02-20 ppm (pigs),0.08-80 ppm (poultry) and 0.02-200 ppm (cattle) to the sole fodder, soas to achieve a daily dosage of from 1 1000 mcg/kg of body weight.

Examples of animals which would be considered include pigs, cattle,poultry for fattening, other poultry such as hens, ducks, geese orturkeys, sheep, rabbits and fish.

Examples of particularly suitable fodder which might contain one of theabove compounds or a physiologically acceptable acid addition saltthereof in the concentrations specified above would include:

for pigs: milk replacement fodder for piglets, sole fodder for piglets(piglet rearing fodder), sole fodder I for fattening pigs up to about 50kq, sole fodder Il for fattening pigs of about 50 kq upwards, solefodder for fattening pigs of about 35 kq upwards;

food supplements for piglets, food supplements I for fattening pigs,food supplement II for fattening pigs, high-protein food supplement forpigs or protein concentrate for pigs (food supplement), and for cattlemilk replacement fodder for rearing calves, food supplement to be addedto skimmed milk for rearing calves, food supplement for rearing calves,skimmed milk replacement fodder I for fattening calves, milk replacementfodder II for fattening calves of about 80 kq upwards, high-energy foodsupplement to be added to skimmed milk for fattening calves, foodsupplement for fattening cattle or high-protein food supplement forfattening cattle;

for sheep: milk replacement fodder for lambs or sole fodder forfattening lambs;

for poultry: sole fodder for fattening geese, food supplement forfattening geese, sole fodder for ducks, sole fodder for ducklings, solefodder for hens in the first weeks of their lives, sole fodder for hens,sole fodder for young hens, sole fodder I for broilers, sole fodder IIfor broilers from about the fifth week of their life onwards, foodsupplement for hens, sole fodder for turkeys, sole fodder for turkeychicks or sole fodder for fattening hens;

for rabbits: sole fodder for fattening rabbits or food supplement forfattening rabbits; and,

for fish: sole fodder for carp or sole fodder for trout or correspondingadditional feed or supplementary feed.

Thus, for example, the concentration of one of the above compounds or aphysiologically acceptable acid addition salt thereof is from 0.02 to200 ppm in sole fodders and from 0.2 to 1000 ppm in food supplements.The feed additive according to the invention differs from theantibacterial substances used hitherto which improve performance byaffecting the flora of the intestines in that it directly influences theendocrinal regulating systems which are involved in the growth process,so as to favor anabolic metabolism.

Moreover, it has a minor problem of residue, i.e. low toxicity, noinhibiting effect on bacterial growth and no dysbiosis and no formationor transmission of resistance.

The feed additive according to the invention differs from the feedadditives known hitherto, in particular, by its preferred effect onimproving the quality of the carcass, i.e. a selective improvement inthe ratio of muscle to fat in favor of the proportion of muscle andprotein.

The following Examples of feed compositions are intended to illustratethe invention (All the quantities given relate to percent by weightunless otherwise stated):

Example 1

    ______________________________________                                        Sole fodder I for fattening pigs up to about 50 kg                            ______________________________________                                        a)     Crude protein  min.       16                                                  Lysine         min.       0.8                                                 Crude fat      max.       8                                                   Crude fibre    max.       6                                                   Starch         min.       33                                                  Calcium        min.       0.7                                                 Phosphorus     min.       0.5                                                 Sodium         min.       0.15                                         b)     Copper         min.       20   mg                                             Zinc           min.       50   mg                                             Vitamin A      min.       4000 IU                                             Vitamin D      min.       500  IU                                      c)     2-(2,6-Dichloroanilino)-2-imidazoline 0.02-20 ppm                      ______________________________________                                    

Example 2

    ______________________________________                                        Milk replacement fodder II for fattening calves                               of about 80 kg upwards (sole fodder)                                          ______________________________________                                        a)    Crude protein  min.   17                                                      Lysine         min.   1.25                                                    Crude fat             15 to 30                                                Crude fibre    max.   2                                                       Crude ash      max.   10                                                      Calcium        min.   0.9                                                     Phosphorus     min.   0.7                                                     Sodium         min.   0.2                                                     Magnesium      min.   0.13                                                    Powdered milk  min.   25                                                b)    Copper         max.   15        mg                                            Vitamin A      min.   8000      IU                                            Vitamin D      min.   1000      IU                                            Vitamin E      min.   20        mg                                      c)    2-(2,6-Dichloroanilino)-2-imidazoline 0.02-200 ppm                      ______________________________________                                    

Example 3

    ______________________________________                                        Cattle fattening fodder II (high-protein food                                 supplement for fattening cattle)                                              ______________________________________                                        a)     Crude protein          30 to 40                                               including:                                                                    Crude protein from                                                            NPN compounds   max.   10                                                     Crude fat       max.   10                                                     Crude fibre     max.   12                                                     Crude ash       max.   12                                                     Calcium                1.6 to 2.4                                      b)     2-(2,6-Dichloroanilino)-2-imidazoline 0.02-200 ppm                     ______________________________________                                    

Example 4

    ______________________________________                                        Sole fodder I for broilers                                                    ______________________________________                                        a)     Crude protein                                                                              min.   22                                                        Methionine   min.   0.45                                                      Total sugar  max.   12                                                        Calcium             0.7 to 1.2                                                Phosphorus   min.   0.6                                                       Sodium              0.12 to 0.3                                        b)     Manganese    min.   50         mg                                             Zinc         min.   50         mg                                             Vitamin A    min.   6000       IU                                             Vitamin D.sub.3                                                                            min.   750        IU                                             Riboflavin   min.   4          mg                                             (Vitamin B.sub.2)                                                             Vitamin B.sub.12                                                                           min.   10         μg                                   c)     2-(2,6-Dichloroanilino)-2-imidazoline 0.08-80 ppm                      ______________________________________                                    

Example 5

    ______________________________________                                        Sole fodder for fattening lambs                                               ______________________________________                                        a)     Crude protein  min.   16                                                      Crude fibre    max.   8                                                       Crude ash      max.   9                                                       Calcium        min.   1                                                       Phosphorus     min.   0.5                                                     (Ca:P ratio not                                                               less than 2:1)                                                         b)     Vitamin A      min.   10000    IU                                             Vitamin D      min.   1250     IU                                             Vitamin E      min.   12       mg                                      c)     2-(2,6-Dichloroanilino)-2-imidazoline 0.02-200 ppm                     ______________________________________                                    

Example 6

    ______________________________________                                        Sole fodder for fattening turkeys                                             ______________________________________                                        a)     Crude protein                                                                              min.   14                                                        Methionine   min.   2                                                         based on                                                                      Crude protein                                                                 Total sugar  max.   12                                                        Calcium             0.7 to 1.7                                                Phosphorus   min.   0.7                                                       Sodium              0.12 to 0.3                                        b)     Manganese    min.   50         mg                                             Zinc         min.   50         mg                                             Vitamin A    min.   8000       IU                                             Vitamin D.sub.3                                                                            min.   1000       IU                                             Riboflavin   min.   4          mg                                             (Vitamin B.sub.2)                                                             Biotin       min.   0.15       mg                                      c)     2-(2,6-Dichloroanilino)-2-imidazoline 0.08-80 ppm                      ______________________________________                                    

What is claimed is:
 1. A method for promoting growth in an animal whichcomprises administering to said animal a growth promoting amount of animido[1,2-a]triazine of the formula ##STR26## wherein: R¹ is phenyl orphenyl which is mono-, di-, or tri-substituted by halogen, methyl,methoxy, or trifluoromethyl, the substituents on said phenyl being thesame or different; and,R² is hydrogen, phenyl, or phenyl which is mono-,or poly-substituted by halogen; or,or a physiologically acceptable acidaddition salt thereof.
 2. A method for promoting growth in an animalwhich comprises administering to said animal a growth promoting amountof8-(2,6-dichlorophenyl)-7-(4-chlorophenyl)-5-oxo-2,3-dihydro-imidazo-[1,2-a]s-triazine,or a physiologically acceptable acid addition salt thereof.